IRF9 prevents CD8<sup>+</sup> T cell exhaustion in an extrinsic manner during acute LCMV infection — ASN Events
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  3. IRF9 prevents CD8+ T cell exhaustion in an extrinsic manner during acute LCMV infection

IRF9 prevents CD8+ T cell exhaustion in an extrinsic manner during acute LCMV infection (#381)

Tamara Suprunenko 1 , Thomas Ashhurst 2 , Magdalena Huber 3 , Nicholas JC King 2 , Iain L Campbell 1 , Markus J Hofer 1 4
  1. School of Life and Environmental Sciences, Marie Bashir Institute for Infectious Diseases and Biosecurity, Charles Perkins Centre and the Bosch Institute, The University of Sydney, Sydney, Australia
  2. Department of Pathology, School of Medical Sciences, Sydney Medical School, Bosch Institute, Sydney Cytometry Facility and Centenary Institute, The University of Sydney, Sydney, Australia
  3. Institute of Medical Microbiology and Hygiene, University of Marburg, Marburg, Germany
  4. Department of Neuropathology, University of Marburg, Marburg, Germany

Interferon regulatory factor 9 (IRF9) is a key component of type I interferon (IFN-I) signaling and critical for the host anti-viral response. Using LCMV-Armstrong (LCMV-Arm), which typically causes acute infection, we show that IRF9-deficient and interferon-alpha receptor (IFNAR)-deficient mice failed to control early viral replication and developed persistent infection.

CD8+ T-cells are critical in mediating the course of viral infection, and are responsible for mediating the clearance of LCMV infection. However, when antigen exposure persists, such as during a chronic viral infection, CD8+ T-cell responses can become suboptimal. This state is termed T-cell exhaustion and is characterised by poor effector function, sustained expression of inhibitory receptors and altered expression of transcription factors. Following infection with LCMV-Arm, virus-specific CD8+ T-cells from both IRF9- and IFNAR-deficient mice had increased expression of co-inhibitory receptors compared to their wild type counterparts. These virus specific T-cells also had markedly reduced production of effector cytokines IFN-g and TNF-a. This demonstrates that IRF9 downstream of IFNAR prevents CD8+ T-cell exhaustion following LCMV-Arm infection.

By adoptive transfer, we demonstrated that this defect in the CD8+ T-cell response was the result of T-cell extrinsic IRF9-deficiency. Given dendritic cells (DCs) are crucial for T-cell activation, we hypothesised that IRF9-dpendent signalling is critical for the functions of DCs. We found that DCs from IRF9- and IFNAR-deficient mice were abnormally activated and had diminished expression of antiviral effector genes. This was accompanied by lack of control of early LCMV replication in DCs.

Our findings demonstrate an important role for IRF9 signaling, downstream of IFNAR, in preventing CD8+ T-cell exhaustion and in stimulating normal activation of DCs.

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